Rapidly soluble drug composition

ABSTRACT

A fast-dissolving pharmaceutical composition comprising micronized (R)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3′-pyrrolidine-1,2′,3,5′-tetrone (hereinafter, referred to as AS-3201). The present pharmaceutical composition has improved dissolution characteristics as well as a good bioavailability.

TECHNICAL FIELD

The present invention relates to a fast-dissolving pharmaceuticalcomposition of(R)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3′-pyrrolidine-1,2′,3,5′-tetrone(hereinafter, referred to as “AS-3201”) having a potent aldose reductaseinhibitory activity.

BACKGROUND ART

AS-3201 is the compound of the following formula. Said compound isdescribed in Example 22 of Japanese Patent No. 2516147 (U.S. Pat. No.5,258,382), Reference Example 12 of JP-A-6-192222 (Chem. Abstr., 122,9860 (1995)), and Experiment of JP-A-8-176105 (Chem. Abstr., 125, 221569(1996)), and its potent aldose reductase inhibitory activities aredisclosed therein.

Example 28 of Japanese Patent No. 2516147 (USP 5258382) describes amethod for preparing specific tablets of AS-3201. That is, it isdescribed therein that AS-3201 (1 g), corn starch (25 g), lactose (58g), crystalline cellulose (11 g), hydroxypropylcellulose (3 g), lightanhydrous silicic acid (1 g) and magnesium stearate (1 g) are blended,granulated and made into 1,000 tablets each weighing 100 mg by aconventional method.

During the studies on methods for preparing AS-3201-containingpharmaceutical compositions having an excellent bioavailability, thepresent inventors have found that the water-solubility of said substanceis extremely low in the range of low pH to the extent of several μg/ml,and therefore, the plasma concentration of AS-3201 varies widely amongthe individuals to be administered.

Under such circumstances, the present inventors have further intensivelystudied, and have found that by using micronized AS-3201 in acomposition, the dissolution characteristics of said substance from thecomposition are remarkably improved, and as a result, anAS-3201-containing fast-dissolving pharmaceutical composition having agood bioavailability can be obtained, and finally have accomplished thepresent invention.

DISCLOSURE OF INVENTION

The present invention provides a fast-dissolving pharmaceuticalcomposition comprising micronized AS-3201.

The terms used in the present specification are explained below.

The “micronized AS-3201” means powders of AS-3201 having a mean particlesize of less than about 20 μm. The “mean particle size” means a particlesize of being at 50% in cumulative particle distribution on weight orvolume basis (ref., HA Lieberman et al., “Pharmaceutical Dosage Forms:Tablets”, Marcel Dekker, Inc., New York, 1990, vol. 2, 174–186; KouichiIINOYA (edit.) “Handbook of Powder and Particle Measurement (inJapanese)”, The NIKKAN KOGYO SHINBUN LTD., 1981, 29–36). The“dissolution test” means a test in which the dissolution of AS-3201 fromtest pharmaceutical compositions in an amount corresponding to 20 mg ofAS-3201 is evaluated according to Paddle method (50 rpm) specified inthe Twelfth Edition of the Pharmacopoeia of Japan, using a 0.2 Mphosphate buffer (pH 6.5, 900 ml) as a test solution, and assayingAS-3201 by spectrophotometry at 300 nm. The “pK_(a1)” means an aciddissociation exponent of an acidic substance at 25° C. in an infinitelydiluted solution thereof. When an acidic substance is a polybasic acid,it means an acid dissociation exponent at the first step ofdissociation. The “water-solubility” means a maximum amount of a solutebeing dissolved in 100 ml of water. The term “about” is used with theintention of including values following said term.

The mean particle size of the micronized AS-3201 is preferably less thanabout 10 um, more preferably less than about 5 μm, and most preferablyin the range of about 0.5 um to about 3 μm.

According to the method disclosed in Japanese Patent No. 2516147 (U.S.Pat. No. 5,258,382), crystals of AS-3201 having a mean particle size ofabout 60 μm to about 120 μm can usually be obtained. The micronizationof AS-3201 crystals is carried out using a mill that is conventionallyused in the pharmaceutical field. Mills are, for example, a fluid energymill such as Jet Mill (manufactured by SEISHIN ENTERPRISE Co., LTD.,Japan), a high speed rotative impact mill such as Sample Mill(manufactured by Hosokawa Micron Corporation, Japan), Pin Mill(manufactured by ALPINE, Germany), or Angmill (manufactured by HosokawaMicron Corporation, Japan), a wet form high speed tumbling triturationmill such as MICROS (manufactured by Nara Machinery Co., Ltd., Japan),and a tumbling mill such as a ball mill. In order to obtain micronizedpowders having a mean particle size of less than about 5 μm, a fluidenergy mill is preferably used. The micronization can be carried out onAS-3201 crystals alone, or on a mixture of AS-3201 crystals and a partor whole of pharmaceutical excipients or carriers, which are used in thepreparation of pharmaceutical compositions.

The AS-3201-containing fast-dissolving pharmaceutical composition of thepresent invention may be solid dosage forms, and includes, for example,tablets, capsules, granules, powders, etc. These pharmaceuticalcompositions can be prepared by mixing micronized AS-3201 withpharmaceutical excipients or carriers such as diluents, disintegrators,binders and lubricants by a conventional method. For example, themixture is granulated by wet-granulation such as high-shear granulation,fluid bed granulation, agitation fluid bed granulation, centrifugalfluid bed granulation, or extrusion granulation, or by dry-granulationsuch as roller compaction or slugging, and then the resulting granulesare put into capsules for capsule preparations, or compressed for tabletpreparations. Alternatively, a mixture of micronized AS-3201 andpharmaceutical excipients or carriers can directly be put into capsulesfor capsule preparations, or compressed for tablet preparations. Thesepharmaceutical compositions may optionally be coated, or mayadditionally contain stabilizers, surfactants, coloring agents,flavoring agents, etc.

The pharmaceutical excipients or carriers may be any ones except forones showing a bad compatibility with AS-3201. The diluents include, forexample, lactose, starch, crystalline cellulose, D-mannitol, sucrose,glucose, erythritol, xylitol, D-sorbitol, anhydrous dibasic calciumphosphate, and calcium sulfate. The disintegrators are, for example,starch, crystalline cellulose, low substituted hydroxypropylcellulose,carmellose, carmellose calcium, sodium carboxymethyl starch,croscarmellose sodium, partly pregelatinized starch, and hydroxypropylstarch. The binders are, for example, acacia, starch,hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol,pullulan, gelatin, ethylcellulose, methylcellulose, carmellose sodium,and dextrin. The lubricants are, for example, magnesium stearate,calcium stearate, stearic acid, sucrose esters of fatty acids, lightanhydrous silicic acid, talc, hydrogenated oil, and macrogol.

The stabilizer may be any pharmaceutically acceptable acidic substanceshaving an acidity more potent than that of AS-3201, i.e.,pK_(a)=5.6–5.8, and preferable acidic substances are ones having apK_(a1) of less than about 4.5 and a water-solubility of larger thanabout 10 g/100 ml at 15° C.–25° C. More preferable acidic substances areones having a pK_(a1) of less than about 3.3 and a water-solubility oflarger than about 50 g/100 ml at 15° C.–25° C. Especially preferableacidic substances are, for example, citric acid, tartaric acid, maleicacid, and phosphoric acid. Among these acidic substances, tartaric acidis most preferable. The content of the acidic substance is preferably inthe range of about 0.5% by weight to about 2.5% by weight. It ispreferable to add a stabilizer in the case of preparing a pharmaceuticalcomposition containing AS-3201 in a ratio of less than about 5% byweight.

The surfactants to be used in the present pharmaceutical compositionare, for example, sorbitan fatty acid esters and polysorbates. Thecoloring agents are, for example, tar color, caramel, and red ironoxide. The flavoring agents are, for example, sweeteners and perfumes.

The dissolution characteristics of the active substance from thecomposition can be remarkably improved by using micronized AS-3201, andby further controlling the combination ratio of pharmaceuticalexcipients or carriers, AS-3201-containing fast-dissolvingpharmaceutical compositions having more improved dissolutioncharacteristics as well as good bioavailability can be obtained. Thecombination ratio of the pharmaceutical excipients or carriers may varydepending on the content of AS-3201. The content of AS-3201 in thepresent fast-dissolving pharmaceutical composition is usually in therange of about 0.5% by weight to about 25% by weight, to the totalweight of the pharmaceutical composition. When the content of AS-3201 isin the range of about 0.5% by weight to 5% by weight to the total weightof the pharmaceutical composition, then the pharmaceutical compositionusually comprises a diluent in a ratio of about 51% by weight—about93.8% by weight, a disintegrator in a ratio of about 5% by weight—about35% by weight, a binder in a ratio of about 0.5% by weight—about 5% byweight, and a lubricant in a ratio of about 0.2% by weight—about 4% byweight. More preferably, the pharmaceutical composition comprises adiluent in a ratio of about 59% by weight—about 88% by weight, adisintegrator in a ratio of about 10% by weight—about 30% by weight, abinder in a ratio of about 1% by weight—about 3% by weight, and alubricant in a ratio of about 0.5% by weight—about 3% by weight. Whenthe content of AS-3201 is more than 5% by weight and less than about 25%by weight to the total weight of the pharmaceutical composition, thenthe present composition usually comprises a diluent in a ratio of about16% by weight—about 84.3% by weight, a disintegrator in a ratio of about10% by weight—about 50% by weight, a binder in a ratio of about 0.5% byweight—about 5% by weight, and a lubricant in a ratio of about 0.2% byweight—about 4% by weight, and more preferably, a diluent in a ratio ofabout 29% by weight—about 73.5% by weight, a disintegrator in a ratio ofabout 20% by weight—about 40% by weight, a binder in a ratio of about 1%by weight—about 3% by weight, and a lubricant in a ratio of about 0.5%by weight—about 3% by weight.

Since AS-3201 has an extremely low water-solubility to the extent ofseveral μg/ml in the range of low pH, there is a correlation between theinitial dissolution rate and the bioavailability of AS-3201-containingpharmaceutical compositions, and compositions having a better initialdissolution rate can show a better bioavailability. From the viewpointof the above, preferable compositions are ones having a dissolutionpercentage of the active substance of 50% or more for 15 minutes afterthe start of the dissolution test, and more preferable pharmaceuticalcompositions are ones having a dissolution percentage of the activesubstance of 80% or more for 15 minutes after the start of thedissolution test.

The AS-3201-containing fast-dissolving pharmaceutical composition of thepresent invention may be packed in a bottle using materials of lowmoisture-permeability or in damp-proof packages such as heat-sealedpackages, if necessary.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing a dissolution pattern of the tablets ofExamples 1 and 2, and Comparative Example 1.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated in more detail by Examples andComparative Example, but the present invention should not be construedto be limited thereto. The mean particle size was measured using a laserdiffraction particle size distribution analyzer (HELOS & RODOS(trademark), manufactured by SYMPATEC GmbH, Germany), and calculatedfrom cumulative particle distribution on volume basis by dry airdispersion method (dispersion air pressure: 0.5 atm).

EXAMPLE 1

Preparation of tablets: AS-3201 160 g Tartaric acid 8 g Lactose 492 gLow substituted hydroxypropylcellulose 300 g Hydroxypropylcellulose 20 gMagnesium stearate 20 g Total 1000 g

AS-3201 crystals were micronized using Single Truck Jet Mill(manufactured by SEISHIN ENTERPRISE CO., LTD., hereinafter abbreviatedas “Jet Mill”) with compression air pressure of 6 kgf/cm² to givepowders having a mean particle size of about 1.5 μm. The micronizedAS-3201 powders thus obtained, lactose, and low substitutedhydroxypropylcellulose were charged into a fluid bed granulator anddrier, and then the mixture was granulated by spraying thereto asolution of tartaric acid in a 5% aqueous hydroxypropylcellulosesolution. The granules were dried, and thereto was added magnesiumstearate, and the mixture was blended in a V-blender. The resultant wascompressed on a rotary tableting machine to give tablets weighing 125 mgand containing 20 mg of AS-3201 each.

EXAMPLE 2

Preparation of Tablets:

AS-3201 crystals were micronized by Sample Mill (manufactured byHosokawa Micron Corporation) to give powders having a mean particle sizeof about 10 μm. The micronized AS-3201 powders thus obtained weregranulated, dried and compressed in the same manner as in Example 1, togive tablets weighing 125 mg and containing 20 mg of AS-3201 each.

COMPARATIVE EXAMPLE 1

Preparation of Tablets:

Non-micronized AS-3201 crystals having a mean particle size of about 87μm were granulated, dried and compressed in the same manner as inExample 1, to give tablets weighing 125 mg and containing 20 mg ofAS-3201 each.

EXPERIMENT 1

Dissolution Test:

The dissolution of the active substance from the tablets obtained inExamples 1 and 2 and Comparative Example 1 was evaluated according toPaddle method (50 rpm) specified in the Twelfth Edition of thePharmacopoeia of Japan, using a 0.2 M phosphate buffer (pH 6.5, 900 ml)as a test solution. The quantitative assay of AS-3201 was carried out byspectrophotometry at 300 nm.

The results are shown in FIG. 1. Each point of FIG. 1 shows the meanvalue of the results in three repeats of the experiments on each tabletof Example 1, Example 2 and Comparative Example 1.

As is shown in FIG. 1, the tablets of Example 1 and Example 2 showremarkably improved dissolution characteristics, as compared with thetablets of Comparative Example 1.

EXAMPLE 3

Preparation of tablets: AS-3201 160 g Tartaric acid 10 g Lactose 600 gLow substituted hydroxypropylcellulose 200 g Hydroxypropylcellulose 20 gMagnesium stearate 10 g Total 1000 g

The above components were treated in the same manner as in Example 1,and compressed to give tablets weighing 125 mg and containing 20 mg ofAS-3201 each. The dissolution percentage of the active substance fromthe tablets thus obtained for 15 minutes after the start of thedissolution test was 72.6%.

EXAMPLE 4

Preparation of tablets: AS-3201 20 g Tartaric acid 8 g Lactose 732 g Lowsubstituted hydroxypropylcellulose 200 g Hydroxypropylcellulose 20 gMagnesium stearate 20 g Total 1000 g

AS-3201 crystals were micronized using Jet Mill with compression airpressure of 6 kgf/cm², and the resultant was charged into a fluid bedgranulator and drier together with lactose and low substitutedhydroxypropylcellulose, and then, the resultant was granulated byspraying thereto a solution of tartaric acid in a 5% aqueoushydroxypropylcellulose solution. The granules were dried, and theretowas added magnesium stearate, and the mixture was blended in aV-blender. The resultant was compressed on a rotary tableting machine togive tablets weighing 125 mg and containing 2.5 mg of AS-3201 each.

The dissolution percentage of the active substance from the tablets thusobtained for 15 minutes after the start of the dissolution test was93.0%.

EXAMPLE 5

Preparation of tablets: AS-3201 80 g Tartaric acid 4 g Lactose 246 g Lowsubstituted hydroxypropylcellulose 150 g Hydroxypropylcellulose 10 gMagnesium stearate 10 g Total 500 g

AS-3201 crystals were micronized using Jet Mill with compression airpressure of 6 kgf/cm², and thereto were added lactose and lowsubstituted hydroxypropylcellulose, and then, the resulting mixture wasblended in a Versatile Mixer for 5 minutes. To the mixture was added asolution of tartaric acid in a 4% aqueous hydroxypropylcellulosesolution, and the mixture was further kneaded for 10 minutes. Themixture was dried, and thereto was added magnesium stearate, and theresulting mixture was compressed on a single-punch tableting machine togive tablets weighing 125 mg and containing 20 mg of AS-3201 each.

The dissolution percentage of the active substance from the tablets thusobtained for 15 minutes after the start of the dissolution test was93.2%.

EXAMPLE 6

Preparation of tablets: AS-3201 144 g Lactose 549 g Low substitutedhydroxypropylcellulose 180 g Hydroxypropylcellulose 18 g Magnesiumstearate 9 g Total 900 g

AS-3201 crystals were micronized using Jet Mill with compression airpressure of 6 kgf/cm², and the resultant was put into a fluid bedgranulator and drier together with lactose and low substitutedhydroxypropylcellulose, and then, the mixture was granulated by sprayingthereto a 5% aqueous hydroxypropylcellulose solution. After drying, tothe granules was added magnesium stearate, and the mixture was blendedin a V-blender. The resultant was compressed on a rotary tabletingmachine to give tablets weighing 125 mg and containing 20 mg of AS-3201each.

The dissolution percentage of the active substance from the tablets thusobtained for 15 minutes after the start of the dissolution test was92.0%.

EXAMPLES 7–9

Preparation of tablets: Ex. 7 Ex. 8 Ex. 9 AS-3201 40 g 40 g 40 gTartaric acid 8 g 8 g 8 g Lactose 712 g 672 g 632 g Low substitutedhydroxy- 200 g 240 g 280 g propylcellulose Hydroxypropylcellulose 20 g20 g 20 g Magnesium stearate 20 g 20 g 20 g Total 1000 g 1000 g 1000 g

AS-3201 micronized using Jet Mill was granulated, dried and compressedin the same manner as in Example 1 to give tablets weighing 125 mg andcontaining 5 mg of AS-3201 each.

The dissolution percentages of the active substance from the tablets ofExamples 7, 8 and 9 for 15 minutes after the start of the dissolutiontest were 91.0%, 94.5% and 92.7%, respectively.

EXAMPLES 10–12

Preparation of tablets: Ex. 10 Ex. 11 Ex. 12 AS-3201 80 g 80 g 80 gTartaric acid 8 g 8 g 8 g Lactose 672 g 632 g 592 g Low substitutedhydroxy- 200 g 240 g 280 g propylcellulose Hydroxypropylcellulose 20 g20 g 20 g Magnesium stearate 20 g 20 g 20 g Total 1000 g 1000 g 1000 g

AS-3201 micronized using Jet Mill was granulated, dried and compressedin the same manner as in Example 1 to give tablets weighing 125 mg andcontaining 10 mg of AS-3201 each.

The dissolution percentages of the active substance from the tablets ofExamples 10, 11 and 12 for 15 minutes after the start of the dissolutiontest were 89.4%, 91.6% and 92.2%, respectively.

INDUSTRIAL APPLICABILITY

As explained above, the AS-3201-containing fast-dissolvingpharmaceutical composition of the present invention has improveddissolution characteristics as well as a good bioavailability.

1. A fast-dissolving pharmaceutical composition in a solid dosage form,comprising micronized(R)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3′-pyrrolidine-1,2′,3,5′-tetrone(hereinafter referred to as “AS-3201”) having a mean particle size of ina range of about 1.5 μm to less than about 10 μm in a ratio of about0.5% by weight to about 25% by weight of the total weight of thepharmaceutical composition, and as a stabilizer at least one acidicsubstance having a pKa less than about 5.6, wherein the acidic substanceis a member selected from the group consisting of citric acid, tartaricacid, maleic acid, and phosphoric acid, and wherein when in adissolution percentage of AS-3201 from the composition is measuredaccording to the Paddle method, 50% or more of the AS-3201 in thecomposition is dissolved with 15 minutes from the start of the method.2. The fast-dissolving pharmaceutical composition according to claim 1,wherein the mean particle size of the micronized AS-3201 is in the rangeof about 1.5 μm to about 5 pin.
 3. The fast-dissolving pharmaceuticalcomposition according to claim 1, wherein the mean particle size of themicronized AS-3201 is in the range of about 1.5 μm to about 3 μm.
 4. Thefast-dissolving pharmaceutical composition according to claim 1, whereinthe solid dosage form is tablets, capsules, granules or powder.
 5. Thefast-dissolving pharmaceutical composition according to claim 1, whereinthe acidic substance is tartaric acid.